Journal
RNA BIOLOGY
Volume 7, Issue 4, Pages 495-503Publisher
LANDES BIOSCIENCE
DOI: 10.4161/rna.7.4.12744
Keywords
Alternative splicing; Scatter factor receptors; Ron; EMT; therapeutic approach; small molecules; antisense oligonucleotides
Categories
Funding
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- European Network of Excellence on Alternative Splicing (EURASNET)
- Fondazione Cariplo
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Alternative splicing is a key molecular mechanism for increasing the complexity of the human transcriptome. Nearly all human genes are regulated by alternative splicing and the deregulation of this process has a causative role in various human diseases, including cancer. The discovery that alternatively spliced isoforms of several genes are expressed selectively in tumour cells opened the exciting possibility that pharmacological treatment of aberrant splicing could lead to new anti-cancer therapeutic approaches. An alternatively spliced isoform of a scatter factor receptor and protooncogene, Ron, accumulates during tumour progression of epithelial tissues and is able to confer an invasive phenotype to the expressing cells. This isoform, called Delta Ron, originates from skipping of exon 11, and this specific splicing event is controlled by the expression level of the splicing factor and proto-oncogene SF2/ASF. Over-expression of SF2/ASF, which occurs frequently in various human tumors, induces the production of Delta Ron and activates the epithelial to mesenchymal transition (EMT), leading to increased cell motility. In this paper, we have used targeted oligonucleotide enhancers of splicing (TOE S) to recruit positive splicing factors to Ron exon 11 and thereby stimulate its inclusion. As an alternative approach, we have used selected indole derivatives that target SF2/ASF splicing activity. Both treatments correct aberrant Delta Ron splicing, restoring the incorporation of Ron exon 11. Notably, indole derivatives are also able to affect the invasive phenotype of the cells. Thus, these treatments may have therapeutic applications for anti-cancer purposes.
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